rs12722477

Variant names:

• chr6-29828599-C-A
• rs12722477
• NM_001384290.1:c.400C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001384290.1(HLA-G):​c.400C>A​(p.Leu134Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 1,613,026 control chromosomes in the GnomAD database, including 12,937 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.15 (1957 hom., cov: 32)
  • Exomes 𝑓: 0.10 (10980 hom.)
• Consequence: HLA-G NM_001384290.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.102
• Publications: 32 publications found

Genes affected

HLA-G (HGNC:4964): (major histocompatibility complex, class I, G) HLA-G belongs to the HLA class I heavy chain paralogues. This class I molecule is a heterodimer consisting of a heavy chain and a light chain (beta-2 microglobulin). The heavy chain is anchored in the membrane. HLA-G is expressed on fetal derived placental cells. The heavy chain is approximately 45 kDa and its gene contains 8 exons. Exon one encodes the leader peptide, exons 2 and 3 encode the alpha1 and alpha2 domain, which both bind the peptide, exon 4 encodes the alpha3 domain, exon 5 encodes the transmembrane region, and exon 6 encodes the cytoplasmic tail. [provided by RefSeq, Jul 2008]

HCG4P8 (HGNC:22927): (HLA complex group 4 pseudogene 8)

HLA-F-AS1 (HGNC:26645): (HLA-F antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0060731173).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.287 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001384290.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-G	NM_001384290.1	MANE Select	c.400C>A	p.Leu134Ile	missense	Exon 3 of 7	NP_001371219.1
	HLA-G	NM_001363567.2		c.415C>A	p.Leu139Ile	missense	Exon 4 of 8	NP_001350496.1
	HLA-G	NM_001384280.1		c.415C>A	p.Leu139Ile	missense	Exon 5 of 9	NP_001371209.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-G	ENST00000360323.11	TSL:6 MANE Select	c.400C>A	p.Leu134Ile	missense	Exon 3 of 7	ENSP00000353472.6
	HLA-G	ENST00000376828.6	TSL:6	c.415C>A	p.Leu139Ile	missense	Exon 4 of 8	ENSP00000366024.2
	HLA-G	ENST00000478355.5	TSL:6	n.400C>A		non_coding_transcript_exon	Exon 3 of 6

Frequencies

GnomAD3 genomes AF: 0.145 AC: 22115 AN: 152090 Hom.: 1951 Cov.: 32

Gnomad AFR AF: 0.224

Gnomad AMI AF: 0.105

Gnomad AMR AF: 0.174

Gnomad ASJ AF: 0.110

Gnomad EAS AF: 0.300

Gnomad SAS AF: 0.204

Gnomad FIN AF: 0.0870

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.0866

Gnomad OTH AF: 0.152

GnomAD2 exomes AF: 0.138 AC: 34138 AN: 247312 AF XY: 0.136

Gnomad AFR exome AF: 0.233

Gnomad AMR exome AF: 0.178

Gnomad ASJ exome AF: 0.113

Gnomad EAS exome AF: 0.296

Gnomad FIN exome AF: 0.0867

Gnomad NFE exome AF: 0.0861

Gnomad OTH exome AF: 0.129

GnomAD4 exome AF: 0.103 AC: 150062 AN: 1460818 Hom.: 10980 Cov.: 53 AF XY: 0.105 AC XY: 75993 AN XY: 726732

African (AFR) AF: 0.230 AC: 7688 AN: 33478

American (AMR) AF: 0.178 AC: 7942 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 2916 AN: 26136

East Asian (EAS) AF: 0.381 AC: 15130 AN: 39700

South Asian (SAS) AF: 0.182 AC: 15712 AN: 86258

European-Finnish (FIN) AF: 0.0884 AC: 4629 AN: 52368

Middle Eastern (MID) AF: 0.143 AC: 823 AN: 5768

European-Non Finnish (NFE) AF: 0.0790 AC: 87813 AN: 1111998

Other (OTH) AF: 0.123 AC: 7409 AN: 60388

GnomAD4 genome AF: 0.145 AC: 22135 AN: 152208 Hom.: 1957 Cov.: 32 AF XY: 0.147 AC XY: 10970 AN XY: 74400

African (AFR) AF: 0.223 AC: 9271 AN: 41526

American (AMR) AF: 0.174 AC: 2668 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.110 AC: 383 AN: 3472

East Asian (EAS) AF: 0.300 AC: 1546 AN: 5160

South Asian (SAS) AF: 0.203 AC: 981 AN: 4826

European-Finnish (FIN) AF: 0.0870 AC: 923 AN: 10606

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.0866 AC: 5889 AN: 68008

Other (OTH) AF: 0.159 AC: 335 AN: 2110

Alfa AF: 0.0663 Hom.: 1199

Bravo AF: 0.155

TwinsUK AF: 0.0704 AC: 261

ALSPAC AF: 0.0804 AC: 310

ESP6500AA AF: 0.219 AC: 660

ESP6500EA AF: 0.0873 AC: 473

ExAC AF: 0.136 AC: 16442

Asia WGS AF: 0.324 AC: 1124 AN: 3478

EpiCase AF: 0.0950

EpiControl AF: 0.0991

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.019	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Pathogenic	3.6	H
PhyloP100		0.10
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.090
Sift	Uncertain	0.027	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.28	B
Vest4		0.032
MPC		1.4
ClinPred		0.076	T
GERP RS		0.56
Varity_R		0.29
gMVP		0.053
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs12722477; hg19: chr6-29796376; COSMIC: COSV64405187; COSMIC: COSV64405187;